tbuckley/cabot-search huggingface dataset:
ER-associated degradation in cystinosis pathogenesis and the prospects of precision medicine
Authors: Varsha Venkatarangan, Weichao Zhang, Xi Yang, Jess Thoene, Si Houn Hahn, Ming Li
Journal: Journal of Clinical Investigation (2023)

Cystinosis is a lysosomal storage disease that is characterized by the accumulation of dipeptide cystine within the lumen. It is caused by mutations in the cystine exporter, cystinosin. Most of the clinically reported mutations are due to the loss of transporter function. In this study, we identified a rapidly degrading disease variant, referred to as cystinosin(7Δ). We demonstrated that this mutant is retained in the ER and degraded via the ER-associated degradation (ERAD) pathway. Using genetic and chemical inhibition methods, we elucidated the roles of HRD1, p97, EDEMs, and the proteasome complex in cystinosin(7Δ) degradation pathway. Having understood the degradation mechanisms, we tested some chemical chaperones previously used for treating CFTR F508Δ and demonstrated that they could facilitate the folding and trafficking of cystinosin(7Δ). Strikingly, chemical chaperone treatment can reduce the lumenal cystine level by approximately 70%. We believe that our study conclusively establishes the connection between ERAD and cystinosis pathogenesis and demonstrates the possibility of using chemical chaperones to treat cystinosin(7Δ).
Fibrosis induced by resident macrophages has divergent roles in pancreas inflammatory injury and PDAC
Authors: John M. Baer, Chong Zuo, Liang-I Kang, Angela Alarcon de la Lastra, Nicholas C. Borcherding, Brett L. Knolhoff, Savannah J. Bogner, Yu Zhu, Liping Yang, Jennifer Laurent, Mark A. Lewis, Nan Zhang, Ki-Wook Kim, Ryan C. Fields, Wayne M. Yokoyama, Jason C. Mills, Li Ding, Gwendalyn J. Randolph, David G. DeNardo
Journal: Nature Immunology (2023)
Black Phosphorus‐Based Conductive Hydrogels Assisted by Electrical Stimulus for Skin Tissue Engineering
Authors: Wenxin Liu, Yingnan Zhu, Zhaofan Tao, Yuxiang Chen, Lei Zhang, Alideertu Dong
Journal: Advanced Healthcare Materials (2023)

Conductive hydrogels have shown great potential in wound healing and skin tissue engineering, owing to their electroactive, mechanical, and chemical properties. However, it still remains as a challenge to incorporate other functions into conductive hydrogels, such as antibacterial ability, controllable drug release, and biodegradability. In this study, a black phosphorus-based conductive hydrogel (HA-DA@BP) is prepared by an amidation reaction coupled with a coordination of Fe3+ -catechol. The hydrogel could be changed from the sol phase to the gel phase under electrical stimulus (ES). The results show that BP could be released under slight acidity, which is cell compatible but could achieve synergistic electrical antibacterial action and promote wound healing. This study proves that BP is a strong candidate for electroactive materials and provides a new insight for the development of BP-based biomedical materials in skin tissue engineering.
Gβγ-SNAP25 exocytotic brake removal enhances insulin action, promotes adipocyte browning, and protects against diet-induced obesity
Authors: Ryan P. Ceddia, Zack Zurawski, Analisa Thompson Gray, Feyisayo Adegboye, Ainsley McDonald-Boyer, Fubiao Shi, Dianxin Liu, Jose Maldonado, Jiesi Feng, Yulong Li, Simon Alford, Julio E. Ayala, Owen P. McGuinness, Sheila Collins, Heidi E. Hamm
Journal: Journal of Clinical Investigation (2023)

Negative regulation of exocytosis from secretory cells is accomplished through inhibitory signals from Gi/o GPCRs by Gβγ subunit inhibition of 2 mechanisms: decreased calcium entry and direct interaction of Gβγ with soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP) receptor (SNARE) plasma membrane fusion machinery. Previously, we disabled the second mechanism with a SNAP25 truncation (SNAP25Δ3) that decreased Gβγ affinity for the SNARE complex, leaving exocytotic fusion and modulation of calcium entry intact and removing GPCR-Gβγ inhibition of SNARE-mediated exocytosis. Here, we report substantial metabolic benefit in mice carrying this mutation. Snap25Δ3/Δ3 mice exhibited enhanced insulin sensitivity and beiging of white fat. Metabolic protection was amplified in Snap25Δ3/Δ3 mice challenged with a high-fat diet. Glucose homeostasis, whole-body insulin action, and insulin-mediated glucose uptake into white adipose tissue were improved along with resistance to diet-induced obesity. Metabolic protection in Snap25Δ3/Δ3 mice occurred without compromising the physiological response to fasting or cold. All metabolic phenotypes were reversed at thermoneutrality, suggesting that basal autonomic activity was required. Direct electrode stimulation of sympathetic neuron exocytosis from Snap25Δ3/Δ3 inguinal adipose depots resulted in enhanced and prolonged norepinephrine release. Thus, the Gβγ-SNARE interaction represents a cellular mechanism that deserves further exploration as an additional avenue for combating metabolic disease.
Negative Predictive Value of Circulating Tumor Tissue Modified Viral (TTMV)-HPV DNA for HPV-driven Oropharyngeal Cancer Surveillance
Authors: Glenn J. Hanna, Scott A. Roof, Jamie Jabalee, Eleni M. Rettig, Rocco Ferrandino, Sida Chen, Marshall R. Posner, Krzysztof J. Misiukiewicz, Eric M. Genden, Raymond L. Chai, John Sims, Elaine Thrash, Scott J. Stern, Noah S. Kalman, Sreenija Yarlagadda, Adam Raben, Lydia Clements, Abie Mendelsohn, John M. Kaczmar, Yadav Pandey, Mihir Bhayani, Piyush Gupta, Charlotte Kuperwasser, Catherine Del Vecchio Fitz, Barry M. Berger
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Human papillomavirus (HPV) is causally linked to oropharyngeal squamous cell carcinoma (OPSCC). Consensus guidelines recommend clinical exams and imaging in decreasing frequency as part of posttreatment surveillance for recurrence. Plasma tumor tissue modified viral (TTMV)-HPV DNA testing has emerged as a biomarker which can inform disease status during surveillance. Experimental Design: This retrospective observational cohort study involved 543 patients who completed curative-intent therapy for HPV-associated OPSCC between February 2020 and January 2022 at eight U.S. cancer care institutions. We determined the negative predictive value (NPV) of TTMV-HPV DNA for recurrence when matched to physician-reported clinical outcome data (median follow-up time: 27.9 months; range: 4.5–154). Results: The cohort included mostly men with a median age of 61 who had locoregionally advanced disease. HPV status was determined by p16 positivity in 87% of patients, with a positive HPV PCR/ISH among 55%; while pretreatment TTMV-HPV DNA status was unknown for most (79%) patients. Patients had a mean of 2.6 tests and almost half had three or more TTMV-HPV DNA results during surveillance. The per-test and per-patient sensitivity of the assay was 92.5% [95% confidence interval (CI): 87.5–97.5] and 87.3% (95% CI: 79.1–95.5), respectively. The NPV for the assay was 99.4% (95% CI: 98.9–99.8) and 98.4% (95% CI: 97.3–99.5), respectively. Conclusions: TTMV-HPV DNA surveillance testing yields few false negative results and few missed recurrences. These data could inform decisions on when to pursue reimaging following first disease restaging and could inform future surveillance practice. Additional study of how pretreatment TTMV-HPV DNA status impacts sensitivity for recurrence is needed.
Primaquine and chloroquine nano-sized solid dispersion-loaded dissolving microarray patches for the improved treatment of malaria caused by Plasmodium vivax
Authors: Qonita Kurnia Anjani, Fabiana Volpe-Zanutto, Khuriah Abdul Hamid, Akmal Hidayat Bin Sabri, Natalia Moreno-Castellano, Xiomara A. Gaitán, Juliana Calit, Daniel Y. Bargieri, Ryan F. Donnelly
Journal: Journal of Controlled Release (2023)

Malaria is a global parasitic infection that leads to substantial illness and death. The most commonly-used drugs for treatment of malaria vivax are primaquine and chloroquine, but they have limitations, such as poor adherence due to frequent oral administration and gastrointestinal side effects. To overcome these limitations, we have developed nano-sized solid dispersion-based dissolving microarray patches (MAPs) for the intradermal delivery of these drugs. In vitro testing showed that these systems can deliver to skin and receiver compartment up to ≈60% of the payload for CQ-based dissolving MAPs and a total of ≈42% of drug loading for PQ-based dissolving MAPs. MAPs also displayed acceptable biocompatibility in cell tests. Pharmacokinetic studies in rats showed that dissolving MAPs could deliver sustained plasma levels of both PQ and CQ for over 7 days. Efficacy studies in a murine model for malaria showed that mice treated with PQ-MAPs and CQ-MAPs had reduced parasitaemia by up to 99.2%. This pharmaceutical approach may revolutionise malaria vivax treatment, especially in developing countries where the disease is endemic. The development of these dissolving MAPs may overcome issues associated with current pharmacotherapy and improve patient outcomes.
Safety, Immunologic, and Clinical Activity of Durvalumab in Combination with Olaparib or Cediranib in Advanced Leiomyosarcoma: Results of the DAPPER Clinical Trial.
Authors: Abdulazeez Salawu, Ben X. Wang, Ming Han, Caryn Geady, Alya Heirali, Hal K. Berman, Thomas D. Pfister, Alberto Hernando-Calvo, Esmail Mutahar Al-Ezzi, Lee-Anne Stayner, Abha A. Gupta, Olubukola Ayodele, Bernard Lam, Aaron R. Hansen, Anna Spreafico, Philippe L. Bedard, Marcus O. Butler, Lisa Avery, Bryan Coburn, Benjamin Haibe-Kains, Lillian L. Siu, Albiruni R. Abdul Razak
Journal: Clinical Cancer Research (2023)

Non-inflamed (cold) tumors such as leiomyosarcoma do not benefit from immune checkpoint blockade (ICB) monotherapy. Combining ICB with angiogenesis or PARP inhibitors may increase tumor immunogenicity by altering the immune cell composition of the tumor microenvironment (TME). The DAPPER phase II study evaluated the safety, immunologic, and clinical activity of ICB-based combinations in pretreated patients with leiomyosarcoma.Patients were randomized to receive durvalumab 1,500 mg IV every 4 weeks with either olaparib 300 mg twice a day orally (Arm A) or cediranib 20 mg every day orally 5 days/week (Arm B) until unacceptable toxicity or disease progression. Paired tumor biopsies, serial radiologic assessments and stool collections were performed. Primary endpoints were safety and immune cell changes in the TME. Objective responses and survival were correlated with transcriptomic, radiomic, and microbiome parameters.Among 30 heavily pretreated patients (15 on each arm), grade ≥ 3 toxicity occurred in 3 (20%) and 2 (13%) on Arms A and B, respectively. On Arm A, 1 patient achieved partial response (PR) with increase in CD8 T cells and macrophages in the TME during treatment, while 4 had stable disease (SD) ≥ 6 months. No patients on Arm B achieved PR or SD ≥ 6 months. Transcriptome analysis showed that baseline M1-macrophage and B-cell activity were associated with overall survival.Durvalumab plus olaparib increased immune cell infiltration of TME with clinical benefit in some patients with leiomyosarcoma. Baseline M1-macrophage and B-cell activity may identify patients with leiomyosarcoma with favorable outcomes on immunotherapy and should be further evaluated.
AI in Medicine—<i>JAMA</i>’s Focus on Clinical Outcomes, Patient-Centered Care, Quality, and Equity
Authors: Rohan Khera, Atul J. Butte, Michael Berkwits, Yulin Hswen, Annette Flanagin, Hannah Park, Gregory Curfman, Kirsten Bibbins-Domingo
Journal: JAMA (2023)

The transformative role of artificial intelligence (AI) in health care has been forecast for decades, 1 but only recently have technological advances appeared to capture some of the complexity of health and disease and how health care is delivered. 2ecent emergence of large language models (LLMs) in highly visible and interactive applications 3 has ignited interest in how new AI technologies can improve medicine and health for patients, the public, clinicians, health systems, and more.The rapidity of these developments, their potential impact on health care, and JAMA's mission to publish the best science that advances medicine and public health compel the journal to renew its commitment to facilitating the rigorous scientific development, evaluation, and implementation of AI in health care.JAMA editors are committed to promoting discoveries in AI science, rigorously evaluating new advances for their impact on the health of patients and populations, assessing the value such advances bring to health systems and society nationally and globally, and examining progress toward equity, fairness, and the reduction of historical medical bias.Moreover, JAMA's mission is to ensure that these scientific advances are clearly communicated in a manner that enhances the collective understanding of the domain for all stakeholders in medicine and public health. 4For scientific development of AI to be most effective for improving medicine and public health requires a platform that recognizes and supports the vision of rapid cycle innovation and is also fundamentally grounded in the principles of reliable and reproducible clinical research that is ethically sound, respectful of rights to privacy, and representative of diverse populations. 2,3,5he scientific development in AI can be viewed through the framework used to describe other health-related sciences. 6n these domains, scientific discoveries begin with identifying biological mechanisms of disease.Then inventions that target these mechanisms are tested in progressively larger groups of people with and without diseases to assess the effectiveness and safety of these interventions.These are then scaled to large studies evaluating outcomes for individuals and populations with the disease.This well-established scientific development framework can work for research in AI as well, with reportable stages as inventions and findings move from one stage to the next.The editors seek original science that focuses on developing, testing, and deploying AI in studies that improve under-
Association of Daytime-Only, Nighttime-Only, and Compound Heat Waves With Preterm Birth by Urban-Rural Area and Regional Socioeconomic Status in China
Authors: Yafei Guo, Peiran Chen, Yanxia Xie, Yanping Wang, Yi Mu, Ruobing Zhou, Yanlin Niu, Xiaoming Shi, Jun Zhu, Juan Liang, Qiyong Liu
Journal: JAMA Network Open (2023)

Associations between heat waves and preterm birth (PTB) have been reported. However, associations of daytime-only, nighttime-only, and compound heat waves with PTB have yet to be explored at a national level. Furthermore, possible heterogeneity across urban-rural communities with different socioeconomic statuses needs to be explored.
Gestational Age and Birth Outcomes in Term Singleton Pregnancies Conceived With Infertility Treatment
Authors: Ira Hamilton, Nicole Martin, James Liu, Emily DeFranco, Robert Rossi
Journal: JAMA Network Open (2023)

Despite the increased perinatal risks associated with pregnancies conceived with infertility treatment, there are no recommendations for timing of delivery among this at-risk population.To identify the gestational age at which the ongoing risks of stillbirth are optimally balanced with the risks of neonatal comorbidities and infant deaths in term singleton pregnancies conceived with infertility treatment.This cohort study used birth and death data from January 1, 2014, to December 31, 2018, in the US obtained from the National Center for Health Statistics. Singleton pregnancies conceived with infertility treatment delivered at term (37-42 weeks' gestation) were eligible for inclusion. The exclusion criteria were deliveries at less than 37 weeks' or at least 43 weeks' gestation and pregnancies with unknown history of infertility treatment, congenital anomalies, pregestational diabetes, pregestational hypertension, gestational hypertension, and preeclampsia. Data were analyzed from July 22, 2022, to June 24, 2023.Gestational age at delivery between 37 and 42 weeks.The primary outcome was optimal timing of delivery. To ascertain this timing, the risk of delivery (rate of neonatal morbidity and infant death) at a given gestational week was compared with the risk of delivery in the subsequent week of gestation for an additional week (rate of stillbirth during the given week per 10 000 ongoing pregnancies plus rate of neonatal morbidity and infant death in the subsequent week of gestation per 10 000 deliveries). The rates of stillbirth, neonatal morbidity, and infant death (within 1 year of life) were compared at each week. Neonatal morbidity included an Apgar score of 3 or lower at 5 minutes, requirement of ventilation for 6 hours or more, neonatal intensive care unit admission, and seizures.Of the 178 448 singleton term pregnancies conceived with infertility treatment (maternal mean [SD] age, 34.2 [5.2] years; mean [SD] gestational age, 39.2 [1.2] weeks; 130 786 [73.5%] were non-Hispanic White patients). The risk of delivery in the subsequent week of gestation was lower than the risk of delivery at both 37 weeks (628 [95% CI, 601-656] vs 1005 [95% CI, 961-1050] per 10 000 live births) and 38 weeks (483 [95% CI, 467-500 vs 625 [95% CI, 598-652] per 10 000 live births). The risks of delivery in subsequent week of gestation significantly exceeded the risk of delivery at 39 weeks (599 [95% CI, 576-622] vs 479 [95% CI, 463-495] per 10 000 live births) and were not significant at 40 weeks (639 [95% CI, 605-675] vs 594 [95% CI, 572-617] per 10 000 live births) and 41 weeks (701 [95% CI, 628-781] vs 633 [95% CI, 599-669] per 10 000 live births).Results of this study suggest that, in pregnancies conceived with infertility treatment, delivery at 39 weeks provided the lowest perinatal risk when comparing risk of delivery at this week of gestation vs the subsequent week of gestation.
Comparative Genomic Analysis Identifies Great–Ape–Specific Structural Variants and Their Evolutionary Relevance
Authors: Bin Zhou, Yaoxi He, Yongjie Chen, Bing Su
Journal: Molecular Biology and Evolution (2023)

Abstract During the origin of great apes about 14 million years ago, a series of phenotypic innovations emerged, such as the increased body size, the enlarged brain volume, the improved cognitive skill, and the diversified diet. Yet, the genomic basis of these evolutionary changes remains unclear. Utilizing the high-quality genome assemblies of great apes (including human), gibbon, and macaque, we conducted comparative genome analyses and identified 15,885 great ape-specific structural variants (GSSVs), including eight coding GSSVs resulting in the creation of novel proteins (e.g., ACAN and CMYA5). Functional annotations of the GSSV-related genes revealed the enrichment of genes involved in development and morphogenesis, especially neurogenesis and neural network formation, suggesting the potential role of GSSVs in shaping the great ape-shared traits. Further dissection of the brain-related GSSVs shows great ape-specific changes of enhancer activities and gene expression in the brain, involving a group of GSSV-regulated genes (such as NOL3) that potentially contribute to the altered brain development and function in great apes. The presented data highlight the evolutionary role of structural variants in the phenotypic innovations during the origin of the great ape lineage.
Probiotics for the management of irritable bowel syndrome: a systematic review and three-level meta-analysis
Authors: Min Chen, Lu Yuan, Chao-Rong Xie, Xiao-Ying Wang, Si-Jia Feng, Xin-Yu Xiao, Hui Zheng
Journal: International Journal of Surgery (2023)

Objective: Previous systematic reviews demonstrated a potentially beneficial effect of probiotics on irritable bowel syndrome (IBS). However, these studies are either affected by the inclusion of insufficient trials or by the problem of dependent data across multiple outcomes, and an overall effect size has not been provided. We aimed to determine the effect of probiotics on IBS through a three-level meta-analysis and clarify potential effect moderators. Methods: We searched Medline, Embase, and Web of Science, screening for randomized controlled trials (RCTs) that examine the effect of probiotics on IBS. The primary outcome was the improvement in the severity of global IBS symptoms at the end of treatment. The secondary outcomes were the improvement in abdominal pain and the quality of life. The effect sizes of the probiotics were measured by using the standardized mean difference (SMD) and pooled by a three-level meta-analysis model. Results: We included 72 RCTs in the analysis. The meta-analysis showed significantly better overall effect of probiotics than placebo on the global IBS symptoms (SMD -0.55, 95%CI -0.76 to -0.34, P &lt;0.001), abdominal pain (SMD -0.89, 95%CI -1.29 to -0.5, P &lt;0.001) and quality of life (SMD 0.99, 95%CI 0.45 to 1.54, P &lt;0.001), respectively. Moderator analysis found that a treatment duration shorter than 4 weeks was associated with a larger effect size in all the outcomes, and Bacillus probiotics had better improvement on the abdominal pain. Conclusions: Probiotics had a short-term effect and a medium effect size on the global IBS symptoms. Treatment duration and types of probiotics affected the effect size of probiotics, and shorter durations and Bacillus probiotics were associated with better treatment effects. Registration: Open Science Framework.
Diagnostic Performance of a Tumor Marker Gene Test to Personalize Serum CA19–9 Reference Ranges
Authors: Mohamad Dbouk, Toshiya Abe, Chiho Koi, Yohei Ando, Helena Saba, Elizabeth Abou Diwan, Anne MacGregor-Das, Amanda L. Blackford, Evelina Mocci, Katie Beierl, Ali Dbouk, Jin He, Richard Burkhart, Anne Marie Lennon, Lori Sokoll, Marcia Irene Canto, James R. Eshleman, Michael Goggins
Journal: Clinical Cancer Research (2023)

Abstract Purpose: CA19–9 synthesis is influenced by common variants in the fucosyltransferase (FUT) enzymes FUT3 and FUT2. We developed a clinical test to detect FUT variants, and evaluated its diagnostic performance for pancreatic ductal adenocarcinoma (PDAC). Experimental Design: A representative set of controls from the Cancer of the Pancreas Screening study was identified for each FUT functional group. Diagnostic sensitivity was determined first in a testing set of 234 PDAC cases, followed by a 134-case validation set, all of whom had undergone resection with curative intent without neoadjuvant therapy. Tumor marker gene testing was performed in the Johns Hopkins Molecular Diagnostics Laboratory. CA19–9 levels were measured in the Hopkins Clinical Chemistry lab. Receiver operating characteristic (ROC) curve analysis was used to evaluate the discriminative ability of CA19–9 alone versus with the gene test. Results: Applying the CA19–9 standard cutoff (&amp;lt;36 U/mL) to all 716 subjects yielded a 68.8% sensitivity in the test set of cases, 67.2% in the validation set, at 91.4% specificity. Applying 99th percentile cutoffs according to each individual's FUT group (3, 34.9, 41.8, and 89.2, for the FUT3-null, FUT-low, FUT-intermediate, and FUT-high groups, respectively) yielded a diagnostic sensitivity for CA19–9 in the first set of cases of 66.7%, 65.7% in the validation set, at 98.9% specificity. ROC analysis for CA19–9 alone yielded an AUC of 0.84; with the tumor marker gene test, AUC improved to 0.92 (P &amp;lt; 0.001). Conclusions: Using a tumor marker gene test to personalize an individual's CA19–9 reference range significantly improves diagnostic accuracy.